Pancreatic ductal adenocarcinoma or PDAC, the fourth-leading cause of cancer deaths in the U.S, is one of the most challenging cancers to detect and treat effectively, having a five-year survival rate of 6%. Standard chemotherapy for PDAC is gemcitabine, which is minimally efficacious and merely prolongs survival for a few months. Novel therapies are desperately needed, and in this proposal, we describe a new approach to shut down the insulin-like growth factor (IGF) axis. The IGF axis interfaces with 3 of the 12 core signaling pathways identified in pancreatic cancer and plays a central role in the etiology of many cancers by stimulating mitogenesis and promoting survival. The role of IGF-II in PDAC is understudied, but evidence suggests that by binding to the IGF-I receptor (IGF1R) or insulin receptor isoform A (IR-A), IGF-II supports tumor growth by stimulating cell division and survival. In contrast, IGF-II binding to the mannose 6- phosphate/IGF-II receptor (M6P/IGF2R) leads to IGF-II internalization and degradation, which down- regulates pericellular IGF-II levels. The M6P/IGF2R also binds lysosomal enzymes via their M6P moieties. Cross-bridging the M6P binding sites on two subunits of the dimeric M6P/IGF2R by bivalent M6P-based ligands, but not by monovalent ligands such as IGF-II, accelerates internalization of the receptor and its bound cargo, including IGF-II, by 3- to 4-fold. This mechanism limits IGF-II availability for binding to he IGF1R/IR-A, which suppresses mitogenic and survival signaling. The long-term goal of this work is to develop novel M6P/IGF2R-based therapy for IGF-II-dependent cancers. This project will test the hypothesis that bivalent M6P ligands can inhibit human pancreatic cancer cell growth by stimulating M6P/IGF2R- mediated disposal of IGF-II as a potential anti-PDAC therapy, by the following Specific Aims: Aim 1: To assess the roles of IGF-II and the IGF2R in regulating proliferation and survival of pancreatic cancer cells. Our working hypothesis is that targeting strategies utilizing soluble M6P/IGF2R as a ligand trap should disrupt IGF-II-driven growth of S2-013 and Capan-1 pancreatic cancer cell lines. Aim 2: To determine whether multivalent M6P-based ligands can inhibit tumorigenic properties in xenograft and genetically engineered mouse models of PDAC. Our working hypothesis is that multivalent M6P ligands will suppress tumorigenic properties in vitro and inhibit development of tumors in vivo. The main in vivo tumor model system will involve orthotopic transplantation of phenotypically marked pancreatic cancer cells into the pancreatic capsule of the nude mouse. We will also test their efficacy in blocking tumor development in a spontaneous model of pancreatic cancer. These studies will serve to validate the approach and justify development of M6P-based multivalent compounds for systemic administration to treat both local and metastatic disease.